title: Physiologically based pharmacokinetic and pharmacodynamic modeling of an antagonist (SM-406/AT-406) of multiple inhibitor of apoptosis proteins (IAPs) in a mouse xenograft model of human breast cancer.
abstract: The inhibitors of apoptosis proteins (IAPs) are a class of key apoptosis regulators overexpressed or dysregulated in cancer. SM-406/AT-406 is a potent and selective small molecule mimetic of Smac that antagonizes the inhibitor of apoptosis proteins (IAPs). A physiologically based pharmacokinetic and pharmacodynamic (PBPK-PD) model was developed to predict the tissue concentration-time profiles of SM-406, the related onco-protein levels in tumor, and the tumor growth inhibition in a mouse model bearing human breast cancer xenograft. In the whole body physiologically based pharmacokinetic (PBPK) model for pharmacokinetics characterization, a well stirred (perfusion rate-limited) model was used to describe SM-406 pharmacokinetics in the lung, heart, kidney, intestine, liver and spleen, and a diffusion rate-limited (permeability limited) model was used for tumor. Pharmacodynamic (PD) models were developed to correlate the SM-406 concentration in tumor to the cIAP1 degradation, pro-caspase 8 decrease, CL-PARP accumulation and tumor growth inhibition. The PBPK-PD model well described the experimental pharmacokinetic data, the pharmacodynamic biomarker responses and tumor growth. This model may be helpful to predict tumor and plasma SM-406 concentrations in the clinic.
authors.affiliation: Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Li
authors.forename: Peng
authors.initials: P
authors.lastname: Zou
authors.forename: Jing-yu
authors.initials: JY
authors.lastname: Yu
authors.forename: Donna
authors.initials: D
authors.lastname: McEachern
authors.forename: Shaomeng
authors.initials: S
authors.lastname: Wang
authors.forename: Duxin
authors.initials: D
authors.lastname: Sun
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D001392:Azocines / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D001559:Benzhydryl Compounds / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D008954:Models, Biological; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D014018:Tissue Distribution; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001392:Azocines; D001559:Benzhydryl Compounds; D051034:Inhibitor of Apoptosis Proteins; C559144:N-benzhydryl-5-(2-(methylamino)propanamido)-3-(3-methylbutanoyl)-6-oxodecahydropyrrolo(1,2-a)(1,5)diazocine-8-carboxamide; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D053181:Caspase 8
keywords: SM-406/AT-406; human breast cancer; mouse xenograft model; multiple inhibitor of apoptosis proteins (IAPs); pharmacodynamic modeling